This invention relates to methods and compositions for treating and preventing mucositis.
Mucositis is the destruction of the oral mucosal epithelium, which results in erythema, ulcerations and severe pain in the oral cavity. Mucositis often arises as a complication of antineoplastic therapy, such as cancer chemotherapy and/or radiation therapy. The painful ulcerative lesions of mucositis can cause patients to restrict their oral intake; as a result, they lose weight and suffer from fever associated with dehydration. Severe mucositis can necessitate the de-escalation of a planned chemo/radio-therapeutic dosing regimen to prevent further damage to the oral mucosa.
An even more serious consequence of mucositis is that the lesions can act as sites of secondary infections and as portals of entry for endogenous oral microorganisms. Mucositis is therefore a significant risk factor for life-threatening systemic infection (septicemia); the risk of systemic infection is exacerbated by concomitant neutropenia, which is another complication associated with chemotherapy. Patients with mucositis and neutropenia have a relative risk of septicemia that is at least four times greater than that of individuals without mucositis.
The overall frequency of mucositis varies; it is influenced by the patient""s diagnosis, age, and level of oral health, as well as the type, dose, and frequency of drug or radiation administration. Approximately 40% of all patients who receive cancer chemotherapy suffer some degree of mucositis, and virtually 100% of patients treated with radiation therapy for head and neck tumors develop mucositis. The frequency of severe mucositis in patients undergoing high risk protocols is over 60%. About 50% of individuals develop lesions severe enough to require modification of their cancer treatment and/or parenteral analgesia.
The development of effective methods for treating and preventing mucositis has been hampered by a lack of understanding of the pathophysiology of this condition, and by the inconsistency in patient response to the medications currently in use.
The invention features methods for treating and preventing mucositis. The invention is based, in part, on the recognition that mucositis is a complex biological process resulting from the cumulative and interactive effects of radiation and/or chemotherapy with epithelial connective tissue and endothelium, pro-inflammatory cytokines, cellular elements within the mucosa and the local oral environment.
We hypothesize that mucositis represents a clinical outcome due to a complex interaction of local tissue (connective tissue, endothelium, epithelium) toxicity, the level of myelosuppression and the oral environment. The local tissue components include an oral mucosa of rapidly renewing stratified squamous epithelium overlying a loose and richly vascular connective tissue base and appear to be responsive to changes in patients"" bone marrow status and, particularly, the degree of granulocytopenia. The oral microbial flora, saliva and functional trauma provide an indigenous environment which impacts on the frequency, severity and course of chemotherapy-associated stomatotoxicity.
It is quite likely that the initial oral tissue response to chemotherapy and radiation occurs at the endothelial and connective tissue level. We believe that free radical formation leads to the disruption of fibronectin with subsequent activation of transcription factors, stimulation of pro-inflammatory cytokine production and tissue damage. A relationship between the presence of tumor necrosis factor-alpha (TNF-xcex1) and IL-1 in serum correlates with the presence of non-hematologic toxicities. It is also likely that injury to endothelial cells occurs simultaneously. Concurrently, damage to the basal epithelial cells prevents their replication. It is unclear whether many of these cells undergo apoptosis or necrosis. An influx of inflammatory cells expressing pro-inflammatory cytokines occurs during the breakdown of the mucosa and peaks just prior to the acme of mucositis. Bacterial colonization of the damaged epithelium occurs and is accelerated by the patient""s myelosuppressed state. Typically the nadir follows a day or so after peak mucositis. Bacterial cell wall products from both gram positive and gram negative organisms likely then penetrate the injured mucosa and further stimulate the release of damaging cytokines. Finally, the mucosa recovers, a process which takes about three weeks in the absence of secondary infection.
According to the invention, mucositis can be treated, or even prevented, by the administration of inflammatory cytokine inhibitors, MMP inhibitors, and/or mast cell inhibitors. The combination of these inhibitors with an anti-inflammatory agent and/or an antimicrobial agent provides an even more effective regime for preventing and treating mucositis.
The invention features a method of reducing or inhibiting mucositis, in a patient suffering from mucositis or at risk for mucositis; the method includes administering to the patient a first therapeutic agent in an amount sufficient to inhibit mucositis, where the first therapeutic agent is an inflammatory cytokine inhibitor, a mast cell inhibitor, an MMP inhibitor, or a combination of these inhibitors. Preferred mast cell inhibitors include degranulation inhibitors, antihistamines, and serine protease inhibitors. A preferred MMP inhibitor is a tetracycline such as minocycline, which used by itself in low doses is an effective mucositis agent that does not primarily act as an antibiotic. Other members of the tetracycline family can be used as well, e.g., chlortetracycline and oxytetracycline. An example of a mucositis that can be reduced or inhibited according to the invention is oral mucositis.
The invention also features a method of treating, inhibiting, or preventing mucositis in the human patient by administering to the patient first and second different therapeutic agents, the first agent being an NSAID (non-steroidal anti-inflammatory), an inflammatory cytokine inhibitor, or a mast cell inhibitor, and the second agent being an inflammatory cytokine inhibitor, a mast cell inhibitor, an MMP inhibitor, an NSAID, or an NO inhibitor. Preferrably at least one of the agents is an NSAID, which is a COX-1 or COX-2 inhibitor; examples of COX-1 inhibitors are indomethacin and flurbriprofin. In other preferred embodiments, the first agent is an inflammatory cytokine inhibitor selected from an IL-6 inhibitor, a TNF-alpha inhibitor, an IL-1 inhibitor, and an interferon-gamma inhibitor. A preferred combination is a TNF-alpha inhibitor combined with an MMP inhibitor such as a tetracycline, eg, minocycline. Exemplary NO inhibitors are aminoguanidine and guanidine. Another TNF-alpha inhibitor that can be used is thalidomide. Mast cell inhibitors can be antihistamines, serine protease inhibitors, or degranulation inhibitors.
In other preferred methods, a third therapeutic agent, in an amount sufficient to inhibit infection, is administered as well; the third therapeutic agent includes an antimicrobial compound. Preferably, the first, second, and third therapeutic agents are administered concurrently.
In another preferred method, the first therapeutic agent, in an amount sufficient to inhibit mucositis, and the third therapeutic agent, in an amount sufficient to inhibit infection, are administered. Preferably, the first therapeutic agent and the third therapeutic agent are administered concurrently.
The mucositis being treated can be induced by antineoplastic therapy; for example, it can be induced by chemotherapy or by radiation therapy. The patient treated with the methods and compositions of the invention can be a cancer patient preparing to undergo chemotherapy or radiation therapy, or a cancer patient currently undergoing chemotherapy or radiation therapy.
The invention further features a pharmaceutical composition for treating oral mucositis that includes (a) a first therapeutic agent including an inflammatory cytokine inhibitor, a mast cell inhibitor, an MMP inhibitor or a combination of these inhibitors; (b) a second therapeutic agent including an anti-inflammatory agent; and (c) a pharmaceutically acceptable carrier. The first and second therapeutic agents are present in amounts sufficient to inhibit mucositis in a patient suffering from mucositis or at risk for mucositis. Preferably, the composition is formulated into a lozenge, a tablet, an oral rinse, an oral paste, or an oral gel. A preferred mast cell inhibitor is an antihistamine; preferred anti-inflammatory agents include non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors. Preferred MMP inhibitors include tetracyclines such as minocycline, tetracycline HCI, or doxycycline. Preferred compositions can also include an anti-ulcer agent, in an amount sufficient to inhibit gastric mucosal injury, and an antimicrobial agent, in an amount sufficient to inhibit infection.